Multiple inhibitory molecules create a profoundly immunuosuppressive environment that is conserved during chronic viral infections in humans and mice, making eliciting effective immunity in this context a challenge. Human persistent viruses highly relevant to health, including HIV, HCV and HBV are restricted to human and non-human primates, which poses great limitations and difficulties to experimental based research. The complexity of the immune system cannot be accurately recreated in vitro and its study requires the use of appropriate whole organisms. We have therefore chosen to use chronic lymphocytic choriomeningitis virus (LCMV) infection of its natural host, the mouse, as a model system. We found that interleukin 6 (IL-6) is produced in a unique biphasic manner during persistent LCMV infection, with late IL-6 being essential for viral control. The underlying mechanism involved IL-6 upregulation of the transcription factor BCL6 in virus-specific CD4 T cells during late chronic infection. This resulted in escalation of T follicular helper cell, germial center and antibody responses. Remarkably, none of the aforementioned IL6 effects could be detected during acute LCMV infection. IL6 shares the transducing co-receptor gp130 with IL6 family of cytokines of which four have been related to the immune system. Ablation of gp130 in T cells during chronic LCMV infection resulted in more profound defects than the sole absence of IL6, as indicated by reduction of virus-specific CD4 T cell numbers and their IL-21 secretion (in addition) to diminished BCL-6 expression. These data indicate that gp130 signaling cytokines, including but not limited to IL6, play a central role in orchestrating CD4 T cells responses and resolving persistent LCMV infection in vivo. We propose to investigate the role of gp130 signaling cytokines and their mechanistic link to CD4 T cell responses during chronic LCMV infection. In Aim #1 we will use anti-IL6R blocking Abs and mice with ablated or loxp-flanked IL6 receptor gene to examine the temporal relevance of IL6 and its direct target cells. We will also use adoptive cell transfer to discern how IL6 drives viral clearance. Aim #2 will study gp130flox/flox mice to investigate the role of gp130 signaling at different times and in specific cell populations during chronic LCMV infection. We will determine the mechanism underlying gp130 control of CD4 T cell numbers by measuring survival and proliferation in mixed bone marrow chimeras. We will also explore the levels and CD4 T cell responsiveness to gp130-cytokines (other than IL6) and we will use shRNA and/or genetically modified mice to investigate their function during chronic LCMV infection. Finally, in Aim #3 we will explore several approaches to harness the gp130-signaling pathway to prevent/attenuate viral persistence. This includes treatment with pan gp130-agonist or selected gp130-cytokines alone or in combination with blockade of inhibitory pathways. Studies in the past three decades using LCMV murine infection have demonstrated high conservation in the immune responses against persistent viruses in mouse and humans. Therefore I am confident that the knowledge gained from the proposed experiments not only will enhanced our understanding of basic immunology but will also point out important players that could regulate immune responses and represent therapeutic targets during chronic viral infections in humans. Furthermore, since LCMV is considered a prototypic arenavirus the proposed studies will increase our understanding of the pathogenesis of human arenaviruses, which cause fatal hemorrhagic fevers.